Mild traumatic brain injury (mTBI), commonly known as concussion, describes an insult to the head that, in turn, causes an injury to the brain. It most often occurs from direct contact to the head, but can also result from indirect injury (e.g., whiplash injury or violent shaking of the head). Individuals who have suffered one brain injury are three times more at risk for a second brain injury and eight times more susceptible for subsequent injuries (see the website www.brainsource.com). Regardless of the severity, the second injury to the brain can be life-threatening if incurred within a short time interval (see Cantu, R. C. and F. O. Mueller, Catastrophic football injuries: 1977-1998, Neurosurgery, 2000, 47(3): p. 673-5; discussion 675-7, and Kelly, J. P., et al., Concussion in sports, Guidelines for the prevention of catastrophic outcome, JAMA, 1991.266(20): p. 2867-9). Also, the damage from successive concussions is cumulative (see Cantu, R. C., Second-impact syndrome, Clinics in Sports Medicine, 17(1):37-44, 1998, and the Catastrophic football injuries paper cited above).
Functions commonly affected by mTBI are cognition, movement, sensation, and emotion (see Table 1, and Mathias, J. L. and J. L. Coats, Emotional and cognitive sequelae to mild traumatic brain injury, Journal of Clinical & Experimental Neuropsychology, 1999, 21(2): p. 200-15, Schoenhuber, R. and M. Gentilini, Anxiety and depression after mild head injury: a case control study, Journal of Neurology, Neurosurgery & Psychiatry, 1988. 51(5): p. 7224, and Rutherford, W. H., J. D. Merrett, and J. R. McDonald, Symptoms at one year following concussion from minor head injuries, Injury, 1979. 10(3): p. 225-30).
Additional risks from a series of concussions include premature senility and Alzheimer's disease (see Fleminger S, Oliver D L, Lovestone S, Rabe-Hesketh S, Giora A., Head injury as a risk factor for Alzheimer's disease: the evidence 10 years on; a partial replication, J Neurol Neurosurg Psychiatry, 2003 July; 74(7):841, Mayeux, R., Ottman, R., Tang, M. X., Noboa-Bauza, L., Marder, K., Gurland, B., and Stern, Y. 1993. Genetic susceptibility and head injury as risk factors for Alzheimer's disease among community-dwelling elderly persons and their first-degree relatives, Ann Neurol 33: 494-501, Graham, D. I., Gentleman, S. M., Lynch, A., and Roberts, G. W. 1995, Distribution of beta-amyloid protein in the brain following severe head injury, Neuropathol Appl Neurobiol 21: 27-34, and Nemetz, P. N., Leibson, C., Naessens, J. M., Beard, M., Kokmen, E., Annegers, J. F., and Kurland, L. T. 1999, Traumatic brain injury and time to onset of Alzheimer's disease: a population-based study, American Journal of Epidemiology 149: 32-40.
TABLE 1Overview of areas impacted by mTBICognitionConcentration memory, judgment moodMovementStrength coordination balanceSensationTactile and special senses (vision)EmotionInstability, impulsivity
Traumatic brain injuries (TBI) are often classified into mild, moderate and severe TBI based on three parameters: 1) the quality and length of change in consciousness, 2) the length of amnesia (memory loss), and 3) the Glasgow Coma Scale (GCS) (Table 2).
TABLE 2TBI classification criteriaLength of LossLength ofGlasgow ComaTBI Classificationof ConsciousnessAmnesiaScale ScoreMild TBI (mTBI)<20 minutes<24 hoursGCS >13+Moderate TBI>20 minutes,GCS 9-12but <6 hoursSevere TBI>6 hoursGCS <8
For a brain injury to be classified as mTBI, the following conditions must be observed: (1) the length of consciousness is less than 20 minutes and amnesia is 24 hours or less, and (2) a GCS score of 13+.
mTBI is estimated to occur in 750,000 of over 2 million cases of TBI annually in the United States alone (see Anonymous, Injury Fact Book, National Center for Injury Prevention and Control: Atlanta, 2002). Based on statistics gathered by the National Center for Injury Prevention Center (NCIPC) at the Center for Disease Control (CDC), mTBIs are most commonly suffered from sports-related injuries, which account for approximately 300,000 injuries annually. The high incidence of mTBI among athletes has raised concern in professional sports organizations. For example, the National Hockey League supports an ongoing concussion study. Age groups most at risk are 15-24 and 75+ years of age. Males are twice as likely to suffer from mTBI as are females. Total costs attributable to mTBI exceed $17 billion annually.
The fundamental dilemma with mTBI lies in the fact that a practical, easy-to-administer diagnostic tool is not yet available. As a result, mTBI is commonly under-, or misdiagnosed, resulting in potential long-term consequences for patients. The present invention is designed to address this specific need.
As was mentioned above, in the United States, approximately 750,000 mild traumatic brain injuries (mTBI) occur every year. Mild traumatic brain injuries remain a serious public health and socioeconomic problem, resulting in long-term disability and death from secondary complications when not properly diagnosed (see Cantu, R. C., Second-impact syndrome. Clinics in Sports Medicine, 17(1):37-44, 1998, Cantu, R. C. and R. Voy, Second-impact syndrome—a risk in any contact sport, Physician and Sports Medicine. 23(6):27, 1995, and Kelly, J. P., J. S. Nichols, C. M. Filley, K. O. Lillehei, D. Rubinstein, and B. K. Kleinschmidt-DeMasters, Concussion in sports, Guidelines for the prevention of catastrophic outcome, JAMA).
Diagnosing mTBI is difficult even in the best setting. The signs and symptoms of mTBI are often very subtle and difficult to detect. Undiagnosed or under-diagnosed mTBI leads to poor clinical management and can often cause cognitive deficits, psychosocial problems, and secondary complications such as depression. See Englander, J., K Hall, T. Stimpson, and S. Chaffin, Mild traumatic brain injury in an insured population: subjective complaints and return to employment, Brain Tnj. 6(2):161-6., 1992, Farm, J. R., W. J. Katon, J. M. Uomoto, and P. C. Esselman, Psychiatric disorders and functional disability in outpatients with traumatic brain injuries, Am J Psychiatry. 152(10):1493-9., 1995, Gomez-Hernandez, R., J. B. Max, T. Kosier, S. Paradiso, and R. G. Robinson, Social impairment and depression after traumatic brain injury, Arch Phys Med Rehabil. 78(12):1321-6., 1997, Gronwall, D., Cumulative and persisting effects of concussion on attention and cognition, in Mild Head Injury, H. S. Levin, Eisenberg, Howard M., Editor, Oxford University Press; New York p. 153-162, 1989, Gronwall, D., Performance changes during recovery from closed head injury, Proc Aust Assoc Neurol. 13:143-7, 1976, Gronwall, D. and P. Wrightson, Delayed recovery of intellectual function after minor head injury, Lancet 2(7881):605-9., 1974, Gronwall, D. and P. Wrightson, Memory and information processing capacity after closed head injury, J Neurol Neurosurg Psychiatry. 44(10):889-95., 1981, Jorge, R. E., R. G. Robinson, S. V. Arndt, A. W. Forrester, F. Geisler, and S. E. Starkstein, Comparison between acute-and delayed-onset depression following traumatic brain injury, J Neuropsychiatry Clin Neurosci. 5(1):43-9., 1993, Stambrook, M., A. D. Moore, L. C. Peters, C. Deviaene, and G. A. Hawryluk, Effects of mild, moderate and severe closed head injury on long-term vocational status, Brain Tnj. 4(2):183-90., 1990, and van der Naalt, J., A. H. van Zomeren, W. J. Sluiter, and J. M. Minderhoud, One year outcome in mild to moderate head injury: the predictive value of acute injury characteristics related to complaints and return to work, J Neurol Neurosurg Psychiatry. 66(2):207-13., 1999. In addition, many cases mTBI are overshadowed by other injuries or by the events surrounding the injury, further confounding accurate diagnoses.
Mild cognitive decline that results from mTBI or degenerative diseases is often very subtle and difficult to detect. Frequently mTBI is overshadowed by other injuries or by the events surrounding the injury. The need for rapid and simple diagnostic testing for early detection is immense. The standard for evaluating possible cognitive deficits is neuropsychological testing. However, neuropsychological testing requires a quiet room void of distractions and the presence of trained personnel to administer, score, and interpret the measures. In addition, these tests may require several hours to perform. In many situations such as sideline assessment of a concussion in sports, these requirements make standard neuropsychological testing impractical.
The lack of diagnostic aids is especially apparent in athletic settings and can lead to repetitive injuries in children and young adults. For sports assessment of mTBI, length of test, ease-of-administration, and immersiveness are the top three criteria for a useable solution. The available approaches have not produced solutions that have all of these attributes.
For example, there are a number of known developmental efforts under way that are directed toward producing a neuropsychological assessment tool. Most of these solutions are software-based and aim to assess the cognitive functioning or impairment of the brain. For example, Neuroscience Solutions uses proprietary technology, sublicensed from Scientific Learning Corporation, based on established principles of “brain plasticity” to address neuropsychological disorders. NuCog is a cognitive assessment tool, developed by researchers in Australia, and is only available for limited use in research and clinical settings.
Of the 2 million traumatic brain injuries per year, [121 eighty percent are classified as “mild” (see Anonymous, Injury Fact Book, 2002, National Center for Injury Prevention and Control: Atlanta.). A substantial number of these patients experience initial objective neuropsychological difficulties involving memory, attention, and executive functioning. See Gronwall, D. and P. Wrightson, Delayed recovery of intellectual function after minor head injury. Lancet, 1974.2(788 1): p. 605-9, Dikmen, S., A. McLean, and N. Temkin, Neuropsychological and psychosocial consequences of minor head injury, J Neurol Neurosurg Psychiatry, 1986. 49(11): p. 1227-32, Dikmen, S. and J. E. Machamer, Neurobehavioral outcomes and their determinants. Journal of Head Trauma Rehabilitation, 1995. 10(1): p. 74-86, Hinton-Bayre, A. D., et al., Concussion in contact sports: reliable change indices of impairment and recovery. J Clin Exp Neuropsychol, 1999. 2 1(1): p. 70-86, Macciocchi, S. N., et al., Neuropsychological functioning and recovery after mild head injury in collegiate athletes. Neurosurgery, 1996. 39(3): p. 510-4, Ponsford, J., et al., Factors influencing outcome following mild traumatic brain injury in adults. Journal of the International Neuropsychological Society, 2000. 6(5): p. 568-79, and Levin, H. S., et al., Neurobehavioral outcome following minor head injury: a three-center study. J Neurosurg, 1987. 66(2): p. 234-43.
A significant subset of patients is left with persistent subjective cognitive complaints that disrupt their social relationships and their ability to resume leisure and work related activities (See van der Naalt, J., Prediction of outcome in mild to moderate head injury: a review. Journal of Clinical &Experimental Neuropsychology, 2001. 23(6): p. 837-51). The importance of the morbidity (i.e., prolonged cognitive deficits, affective and personality changes) and mortality (i.e., second impact syndrome) produced by mTBI has become increasingly appreciated. See Cantu, R. C. and F. O. Mueller, Catastrophic football injuries: 1977-1998. Neurosurgery, 2000.47(3): p. 673-5; discussion 675-7, Cantu, R. C., Head and spine injuries in youth sports. Clinics in Sports Medicine, 1995. 14(3): p. 517-32, Cantu, R. C., Second-impact syndrome. Clinics in Sports Medicine, 1998. 17(1): p. 37-44, Erlanger, D. M., et al., Neuropsychology of sports-related head injury: Dementia Pugilistica to Post Concussion Syndrome. Clinical Neuropsychologist, 1999.13(2): p. 193-209, and Kelly, J. P., et al., Concussion in sports. Guidelines for the prevention of catastrophic outcome. JAMA, 1991. 266(20): p. 2867-9.
There is good evidence that repetitive concussions result in long-term cognitive deficits and structural damage to the brain. See Cantu, R. C., Second-impact syndrome. Clinics in Sports Medicine, 1998. 17(1): p. 37-44, Kelly, J. P., et al., Concussion in sports. Guidelines for the prevention of catastrophic outcome. JAMA, 1991. 266(20): p. 2867-9, and Cantu, R. C. and R. Voy, Second-impact syndrome—a risk in any contact sport. Physician and Sports Medicine, 1995. 23(6): p. 27.
When a second concussion occurs prior to recovery from the first, rapid onset of cerebral edema and death can occur (See Cantu, R. C. and F. O. Mueller, Catastrophic football injuries: 1977-1998. Neurosurgery, 2000.47(3): p. 673-5; discussion 675-7, Cantu, R. C., Head and spine injuries in youth sports. Clinics in Sports Medicine, 1995. 14(3): p. 517-32, Cantu, R. C., Second-impact syndrome. Clinics in Sports Medicine, 1998. 17(1): p. 37-44, Erlanger, D. M., et al., Neuropsychology of sports-related head injury: Dementia Pugilistica to Post Concussion Syndrome. Clinical Neuropsychologist, 1999. 13(2): p. 193-209, and Kelly, J. P., et al., Concussion in sports. Guidelines for the prevention of catastrophic outcome. JAMA, 1991. 266(20): p. 2867-9), particularly for athletes prematurely returning to play.
In addition to these young adult populations, traumatic brain injury peaks in the aged population (See Frankowski, R. F., J. F. Annegers, and S. Whitman, Part 1: The descriptive epidemiology of head trauma in the United States. In: D. P. Becker, I T Povlishock (Eds.). Central Nervous System Trauma Status Report, 1985). With the escalating aging of the population, it has become imperative to develop efficient and accurate methods to diagnose mTBI in older adults. Approximately 21% of the U.S. population is older than age 55, and this will increase to 30% by the year 2025 (See Commerce, U.S.D.o., Statistical Abstract of the United States 1997. 1997, U.S. Department of Commerce, Bureau of the Census). The “oldest-old” (i.e. persons ^85 years) are increasing at the fastest rate.
Early detection of mTBI is critical to patient education and treatment and could potentially prevent secondary complications of depression and anxiety. Depression is a common secondary complication of mTBI. See Fenton, G., et al., The postconcussional syndrome: social antecedents and psychological sequelae. British Journal of Psychiatry, 1993. 162: p. 493-7, Mathias, J. L. and J. L. Coats, Emotional and cognitive sequelae to mild traumatic brain injury. Journal of Clinical & Experimental Neuropsychology, 1999. 21(2): p. 200-15, Schoenhuber, R. and M. Gentilini, Anxiety and depression after mild head injury: a case control study. Journal of Neurology, Neurosurgery & Psychiatry, 1988. 51(5): p. 722-4, Rutherford, W. H., J. D. Merrett, and J. R. McDonald, Symptoms at one year following concussion from minor head injuries. Injury, 1979. 10(3): p. 225-30, Levin, H. S., et al., The neurobehavioural rating scale: assessment of the behavioural sequelae of head injury by the clinician. Journal of Neurology, Neurosurgery & Psychiatry, 1987. 50(2): p. 183-93, and Levin, H. S., F. C. Goldstein, and E. J. MacKenzie, Depression as a secondary condition following mild and moderate traumatic brain injury. Seminars in Clinical Neuropsychiatry, 1997(2): p. 207-215.
Mittenberg and colleagues compared the effectiveness of standard hospital treatment and discharge instructions versus education concerning the symptoms and their management in mTBI patients. See Mittenberg, W., et al., Cognitive-behavioral prevention of postconcussion syndrome. Archives of Clinical Neuropsychology, 1996: p. 139-145. At six months postinjury, 28% percent of patients who received standard treatment met ICD-IO criteria for post-concussion syndrome, compared to only 11% of the preventative treatment group. Patients in the preventative group also reported significantly shorter overall symptom duration, fewer symptoms, fewer symptomatic days in the previous week, and lower symptom severity levels. One implication of this research is that early detection could lead to interventions to mitigate the morbidity associated with mTBI.
The diagnosis of mTBI is very challenging. This difficulty is largely a result of the continuing debate over the clinical definition of concussion. Most physicians agree on the physical signs and symptoms of a moderate and severe TBI (measured by the Glasgow Coma Scale (GCS) score; severe =3-8 and moderate=9-12), which are characterized by alterations in the level of consciousness. [36j However, patients with a mild TBI (GCS 13-15) by definition have almost no mental status changes profound enough to change their GCS score, and fewer than 10% result in an initial loss of consciousness. See Cantu, R. C., Head injuries in sport. British Journal of Sports Medicine, 1996. 30(4): p. 289-96, and Cantu, R. C., Reflections on head injuries in sport and the concussion controversy. Clinical Journal of Sport Medicine, 1997. 7(2): p. 83-4. Many of these patients do not initially seek medical attention or are under-diagnosed by the medical community, making the determination of true incidence impossible. Even when the diagnosis is suspected, patients are not being hospitalized for mTBI as often as in the past, indicating the need for greater surveillance and diagnosis of these cases in the emergency room and outpatient primary care facilities. See Thurman, D. and J. Guerrero, Trends in hospitalization associated with traumatic brain injury. [comment]. JAMA, 1999.282(10): p. 954-7.
The understanding of mTBI is further complicated by a lack of biomechanical understanding of the forces and deformations that lead to mild cognitive deficits. Although mechanical tolerances have been proposed for moderate and severe TBI, determination of thresholds for mTBI is complicated by poor patient recounts and delayed or inaccurate clinical diagnoses. See Lighthall, J. W., J. W. Melvin, and K. Ueno, Toward a biomechanical criterion for functional brain injury. Society of Automotive Engineers, Inc., 1989, and Margulies, S. S. and L. E. Thibault, A proposed tolerance criterion for diffuse axonal injury in man. Journal of Biomechanics, 1992. 25(8): p. 917-23. Early and reliable diagnosis of mTBI may not only assist the patient with rehabilitation and improved outcome, but it will also provide a tool to correlate the acute response to a mild insult with the mechanical circumstances of the injury.
Neuropsychological testing has proven useful in detecting the often subtle changes resulting from mTBI. See Dikmen, S., A. McLean, and N. Temkin, Neuropsychological and psychosocial consequences of minor head injury. J Neurol Neurosurg Psychiatry, 1986. 49(11): p. 1227-32, Hinton-Bayre, A. D., et al., Concussion in contact sports: reliable change indices of impairment and recovery. J Clin Exp Neuropsychol, 1999. 2 1(1): p. 70-86, Levin, H. S., et al., Neurobehavioral outcome following minor head injury: a three-center study. J Neurosurg, 1987. 66(2): p. 234-43, and Leininger, B. E., et al., Neuropsychological deficits in symptomatic minor head injury patients after concussion and mild concussion. J Neurol Neurosurg Psychiatry, 1990. 53(4): p. 293-6.
Table 3 shows results of representative studies conducted in the United States that have prospectively recruited patients with mTBI as opposed to retrospectively recruiting those patients who have complaints and thus introducing a selection bias. The results of these studies indicate cognitive impairments in the initial days that can be detected by formal neuropsychological testing.
TABLE 3Authors/Cognitive OutcomeMeasuresFindingsBarth et al., 1983/WechslerAt 3 months postinjury, 44 pts (57%)Adult Intelligence Scale-R orhad mild-severe impairments onWechsler Intelligence Scale forHaistead-Reitan.Children-R, Halstead-ReitanNeuropsychological Test Battery,Wide Range Achievement Test,Wechsler Memory ScaleDikmen et al., 1986/Haistead-Pts significantly poorer inReitan Neuropsychological Testconcentration and delayed verbalBattery, Wechsler Memory Scale,memory.Selective Reminding TestGoldstein et al., 2000/CaliforniaMild TBI pts. 50 years and olderVerbal Learning Test, Continuousexhibited performance, comparableRecognition Memory, Controlledto normal controls, on mostOral Word Association,measures within 2 months post-Trailmaking, Digit Span, Visualinjury. Word fluency under timedNaming, Wisconsin Card Sortingconditions, however, wasTest.selectively impaired.Hugenholtz et al., 1988/Simple1.Within 3 days postinjury andReaction Time (PT): Pressup to 3 months postinjury,response key with dominant handno significant differencesto a single stimulus (e.g.,between pts and controls oncircle); Choice RT: PressSimple RI taskresponse key with dominant hand2.Up to 17 days postinjury,to a target stimulus (e.g.,pts significantly slowerwhite circle), and respond withthan controls on Easynon-dominant hand for otherChoice RI task but not atshapes (e.g. white square, white1 and 3 months postinjurytriangle); Complex: Press3.Within 3 days postinjury andresponse key with dominant handup to 1 month postmjury, ptsto a target stimulus (e.g.,significantly slower thanwhite circle with horizontalcontrols on Complex Choicelines) and respond with non-RI task but not at 3dominant hand for other shapes,months postinjurycolors, and line orientations(e.g., white circle withvertical lines, blue circle withhorizontal lines)Levin et al., 1987/Digit Span,1.At 1 week postinjury, ptsMemory for animal names (Mattis-had significantly impairedKovner), Benton Visual Retentionattention, memory, andTest, Digit Symbol, Pacedvisuomotor and informationAuditory Serial Addition Taskprocessing speed (76%-87% of57 pts below control meanperformance in each domain)2.At 1 month postinjury, nosignificant differencesbetween pts and controls inGalveston and the Bronx; Ptsin San Diego exhibitedrecovery of memory butcontinuing difficulties withattention and visuomotor andinformation processing speed3.At 3 months postinjury, ptsat all 3 centers were notsignificantly different fromcontrols, except digit spanwhich was lower in SanDiego pts relative tocontrolsMcAllister et al., 1999/Trail1.At 1 to 5 weeks postinjury,Making, Controlled Oral Wordpts significantly slower inFluency Test, Continuoussimple reaction time andPerformance Test, Stroop Colorreaction time underWord Test, California Verbaldistraction.Learning Test, Facial Memory,2.No significant differences inWorking Memory Testword fluency, verbal andvisual memory, or othermeasures of attentionRimel et al., 1981/Wechsler1.At 3 months postinjury, ptsScales of Intelligence,exhibited mild deficitsWechsler Memory Scale,involving attention-Halstead-Reitan Neuropsycho-concentration and problem-logical Test Battery, WidesolvingRange Achievement Test2.No significant impairments,based on published norms,in overall intellectualfunctioning and academicachievement
However, the practicality of neuropsychological testing is limited, as it requires a quiet room, few distractions, and trained personnel to administer, score, and interpret the measures. These conditions are rarely available when most mTBI patients need to be evaluated in the initial days postinjury. In addition, these tests may require several hours to perform. In many situations, such as sideline assessment of concussion or in a busy emergency department, these requirements make standard neuropsychological testing impractical. Moreover, testing in doctors' offices and other non-specialized medical facilities is currently limited due to the specialized training and time required to administer these tests. A concise, portable test that maintains sensitivity for mTBI would allow better management of these patients and provide marked improvement in disease surveillance and outcomes.
Papers have been published relating to virtual reality and neuroscience. Exemplary papers include “VIRTUAL REALITY IN NEUROSCIENCE: A SURVEY”, Giuseppe Riva, Virtual Environments in Clinical Psychology and Neuroscience, Ios Press: Amsterdam, Netherlands, “Virtual Reality and Cognitive Assessment and Rehabilitation: The State of the Art”, Albert A. Rizzo and J. Galen Buckwalter, Ios Press: Amsterdam, Netherlands, and “Virtual Environments in Neuropsychological Assessment and Rehabilitation”, F. D. Rose, E. A. Attree and B. M. Brooks, Ios Press: Amsterdam, Netherlands, all of which generally discuss the use of virtual reality in neuroscience, However, no systems are discussed in these papers that provide for a portable audio-visually immersive evaluation tool.
Thus, although computer-based neuropsychological tests for mTBI evaluation are available, none of these systems provide an immersive, portable, site-of-injury format The need for rapid, simple and convenient diagnostic testing for early detection of mTBI is immense.